The long-term goal of this research has been and remains an understanding of how hormones effect cyclic AMP metabolism in cells and the consequences which follow such alterations in the levels of cyclic AMP. During this grant period we would like to focus upon and extend our studies with the highly differentiated human lung fibroblast WI-38 and its SV-40 transformed counterpart, WI-38-VA13-2RA (VA13). Specifically, we propose to exploit the two systems, which have very different control properties, so as to be able to determine the relative and absolute contributions of the adenyl cyclase system, cyclic nucleotide phosphodiesterase activities, cyclic AMP escape, cyclic GMP metabolism, and other factors to the changes in cyclic AMP levels engendered by hormones. Further, we will attempt to quantitate cyclic AMP turnover in intact WI-38 and VA13. Another prime objective will be an endeavor to determine the relationships (if any) between defective cyclic AMP and cyclic GMP metabolism and the losses of differentiated function associated with transformation. We will also attempt to identify the factors responsible for changes in the responsiveness of the cell strains to hormones (as expressed by alterations in cyclic nucleotide metabolism), including an investigation into the hypothesis that such changes may be, at least in part, involved in viral transformation. BIBLIOGRAPHICAL REFERENCES: Chlapowski, F.J., and Butcher, R.W., Cyclic AMP metabolism of some fibroblastic and epithelial cells in vitro. In: Regulation of Function and Growth of Eukaryotic Cells by Intracellular Cyclic Nucleotides, NATO Advanced Study Institute, J.E. Dumont, B. Brown, and N. Marshall, Eds., Plenum Press, N.Y., pg. 359 (1976). Kelly, L.A., and Butcher, R.W., Liability of catecholamine effects on cyclic AMP levels in cultured fibroblasts. Fed. Proc., 35:609 (1976).